1. Disseminated Intravascular Coagulation (DIC)

2. Vessel wall Vessel wall Platelets Platelets Coagulation factors Coagulation factors Coagulation & hemostasis

3. Cellular system: Monocyte/ Macrophage Cellular system: Monocyte/ Macrophage Anticoagulants in plasma （ TFPI,AT Ⅲ,heparin co-factor II ） Anticoagulants in plasma （ TFPI,AT Ⅲ,heparin co-factor II ） Protein C system Protein C system Fibrinolytic system Fibrinolytic system Anticoagulation

4. Definition of DIC

5. Disseminated intravascular coagulation (DIC) is a complex systemic thrombohemorrhagic disorder involving the generation of intravascular fibrin and the consumption of procoagulants and platelets. The resultant clinical condition is characterized by intravascular coagulation and hemorrhage. Disseminated intravascular coagulation (DIC) is a complex systemic thrombohemorrhagic disorder involving the generation of intravascular fibrin and the consumption of procoagulants and platelets. The resultant clinical condition is characterized by intravascular coagulation and hemorrhage.Definition

6. Causes of DIC

7. The Accepted Disease Entities Generally Associated with DIC Sepsis/severe infection Sepsis/severe infection Malignancy Malignancy solid and myeloproliferative malignancies solid and myeloproliferative malignancies Obstetric complications Obstetric complications Amniotic fluid embolism, Abruptio placentae Amniotic fluid embolism, Abruptio placentae Retained dead fetus syndrome Retained dead fetus syndrome Trauma (neurotrauma),Organ destruction, Burns Trauma (neurotrauma),Organ destruction, Burns Severe hepatic failure Severe hepatic failure Rheumatologic illness Rheumatologic illness Adult Stills disease, Lupus Adult Stills disease, Lupus Vascular abnormalities Vascular abnormalities Kasabach-Merritt syndrome, Large vascular aneurysms Kasabach-Merritt syndrome, Large vascular aneurysms Hemolysis Hemolysis

8. The diseases which associated with DIC always have one or more triggering factors that can activate clotting factors and intravascular coagulation. ① Release TF ② VEC injury ③ LPS ④ Ag-Ab complex Triggering factors ⑤ Protease ⑥ Microparticles ⑦ Pathogenic Microbes (viruses)

9. Pathogenesis of DIC

10. Activation of coagulation Activation of coagulation Disabled anticoagulant mechanism Disabled anticoagulant mechanism Impaired fibrinolysis Impaired fibrinolysisPathophysiology

11. Activation of coagulation Tissue damage Tissue damage Endothelial disruption Endothelial disruption Hemolysis Hemolysis Leukemia Leukemia Other procoagulant molecules enter the vascular system Other procoagulant molecules enter the vascular system

12. HS TM collagen Anticoagulation actions of Endothelial cells Ⅸ a 、Ⅹ a 、 T TF/ Ⅶ a 、Ⅹ a TFPI Thrombin （ T ） cleavage of Ⅴ、Ⅷ PL PL aggregation  PC t-PA u-PA PGI 2 APC PAI Negative charge surface T endocytosis

13. Procoagulant activities of injured endothelial cells Activation of coagulation PL activation PAI  t-PA TF vWF ET collagen Fibrin Thrombin （ T ） TF/VIIa TNF 、 IL-1 、 PAF TXA 2  PGI 2 FN VN WBC Back PL adhesion/aggregation

14. Suppression of anticoagulant pathways Antithrombin activity is reduced Antithrombin activity is reduced Protein C pathway is incapacitated Protein C pathway is incapacitated TFPI is another anticoagulant mechanism that is disabled TFPI is another anticoagulant mechanism that is disabled

15. Impaired fibrinolysis Experimental and clinical studies indicate that during DIC, the fibrinolytic system is largely suppressed at the time of maximal activation of coagulation. This inhibition of fibrinolysis is caused by a sustained rise in the plasma level of plasminogen activator inhibitor-1 (PAI-1), the principal inhibitor of the fibrinolytic system.

16. Plasminogen Extrinic activators EC Pro-PA enzymes t-PA, u-PA Secretion Urine （ UK ， u-PA ） Bile （ bilokinase ） Latex 、 saliva 、 tear Tissue lung 、 prostate 、 uterus Blood cell RBC, Platelet Thrombolytic drugs Streptokinase (SK) Urokinase (UK) rt-PA Proteolyses fibrinogen, fibronectin, laminin, thrombospondin ； Activates collagenases. Plasmin PAI-1 PAI-2 PAI-3 Histidine-rich glycoprotein （ HRG ） Intrinic activators Coagulation ⅪaⅪa ⅡaⅡa ⅫaⅫa Ⅻ KK PK VEC-HK α 2 -plasmin inhibitor (α 2 -PI) α 2 - macroglobin (α 2 –MG) Secondary Fibrinolysis Exogenous activators

17. Proinflammatory cytokines Vascular endothelial cells Mononuclear cells TF expression Impairment of anticoagulant mechanisms PAI-1 mediated inhibition of fibrinolysis Intravascular Fn formation Insufficient Fn removal Fibrin deposition Schematic representation of pathogenetic pathways in DIC

18. Predisposing factors to DIC

19. Impairment of reticuloendothelial system Impairment of reticuloendothelial system There is good evidence that most of the products of intravascular coagulation (free fibrin, prothrombinase, PF3), as well as various initiators of the process (endotoxin, tissue fragments, antigen-antibody complexes, thromboplastins, red cell stroma) are removed from the circulation by the reticuloendothelial system. The hepatic cells are of primary importance in the clearance of activated coagulation factors (IXa, Xa and XIIa). It has been suggested that, in DIC, various substances saturate or block the clearance function of reticuloendothelial system in a manner comparable to that produced experimentally in the general Shwartzman reaction (GSR) in animals. There is good evidence that most of the products of intravascular coagulation (free fibrin, prothrombinase, PF3), as well as various initiators of the process (endotoxin, tissue fragments, antigen-antibody complexes, thromboplastins, red cell stroma) are removed from the circulation by the reticuloendothelial system. The hepatic cells are of primary importance in the clearance of activated coagulation factors (IXa, Xa and XIIa). It has been suggested that, in DIC, various substances saturate or block the clearance function of reticuloendothelial system in a manner comparable to that produced experimentally in the general Shwartzman reaction (GSR) in animals. Reticuloendothelial system is suppressd by glucocorticoid or in the patients with liver diseases. Reticuloendothelial system is suppressd by glucocorticoid or in the patients with liver diseases.

20. Hemostasis is intimately related to liver function, because most coagulation factors are synthesized by liver parenchymal cells and the liver's reticuloendothelial system serves an important role in the clearance of activation products. The extent of coagulation abnormalities depends upon the degree of disturbed liver function. Acute or chronic hepatocellular diseases may display decreases in the vitamin K-dependent factors (prothrombin; factors VII, IX, and X; proteins C and S), whereas other parameters remain normal. Acute or chronic hepatocellular diseases may display decreases in the vitamin K-dependent factors (prothrombin; factors VII, IX, and X; proteins C and S), whereas other parameters remain normal. Patients with hepatic failure may present with the entire spectrum of factor deficiencies and may even develop DIC. Patients with hepatic failure may present with the entire spectrum of factor deficiencies and may even develop DIC. Patients with liver cirrhosis have a wide spectrum of abnormalities. Except for factor VIII:C and von Willebrand factor, all procoagulant and inhibitory factors are decreased, which is a reflection of impaired protein synthesis. Abnormal fibrinogen and prothrombin molecules can be identified. Platelets are quantitatively and qualitatively altered, and most patients develop DIC. Patients with liver cirrhosis have a wide spectrum of abnormalities. Except for factor VIII:C and von Willebrand factor, all procoagulant and inhibitory factors are decreased, which is a reflection of impaired protein synthesis. Abnormal fibrinogen and prothrombin molecules can be identified. Platelets are quantitatively and qualitatively altered, and most patients develop DIC. Hepatic dysfunction

21. Hypercoagulable state It has been found that the platelet and several kinds of clotting factors (factor I, II, VII, VIII, IX and X, etc.) in blood are increased, while the substances with the action of anticoagulation and with the activity of fibrinolysis are deceased. For instance, the blood in pregnancy after 4 months bigins to increase coagulability, which is most marked in the terminal stage of pregnancy. Therefore the incidence of DIC is elevated in obstetrical accidents. In addition, acidosis, common in some patients, promotes the activation of clotting cascade by reducing the pH of the blood.

22. Shock usually accompanies disorder of microcirculation which is manifested by stasis of blood flow, aggregation of blood cells and appearance of sludging, stasis of the microcirculation permits activated clotting factors to accumulated in one region making it easier to develop into a state of DIC. The stasis of blood in giant hemangioma may somehow contribute to the development of DIC. Disorder of microcirculation

23. Inhibition of fibrinolysis Aging, smoking, pregnandiacy, diabetes. Aging, smoking, pregnandiacy, diabetes. Using antifibrinolytic agents like EACA and PAMBA Using antifibrinolytic agents like EACA and PAMBA

24. Main Features of DIC

25. Include petechiae and purpura (found in most patients), hemorrhagic bullae, wound bleeding; especially oozing from a surgical or traumatic wound is common in patients who have undergone surgery or suffered trauma. Bleeding

26. The average patient with DIC usually bleeds from at least three unrelated sites and any combination may be seen. Bleeding

27. Bleeding causes: ▲ Clotting factors consumption ▲ FDP generation ▲ Activation of fibrinolytic system ▲ Vessel damage Bleeding

28. Excess bleeding Excess bleeding Thrombus formation results in a diminished return of venous blood to the heart Thrombus formation results in a diminished return of venous blood to the heart Activation of the kinin system leads to increased vascular permeability, hypotension, andshock Activation of the kinin system leads to increased vascular permeability, hypotension, andshock Creation of FDP result in enhanced vasodilation Creation of FDP result in enhanced vasodilation Myocardial infarction Myocardial infarction Shock

29. Organ damage / failure Impaired blood flow caused by microvascular thrombosis Impaired blood flow caused by microvascular thrombosis Ischemia reperfusion injury Ischemia reperfusion injury Systemic inflammatory response syndrom Systemic inflammatory response syndrom Multiple organ dysfunction syndrome Multiple organ dysfunction syndrome Pathogenesis

30. Organ damage / failure Kidneys – renal damage seen in 25% of DIC cases in one series Liver – hepatic dysfunction in 19% Lungs – respiratory dysfunction in 16%

31. A disorder in which narrowing or obstruction of small blood vessels results in distortion and fragmentation of erythrocytes, hemolysis, and anemia. A disorder in which narrowing or obstruction of small blood vessels results in distortion and fragmentation of erythrocytes, hemolysis, and anemia. It is identified by the finding of anaemia and schistocytes ("bite cells") on microscopy of the blood film. It is identified by the finding of anaemia and schistocytes ("bite cells") on microscopy of the blood film. Microangiopathic hemolytic anemia

33. Primary diseases tissue injury VEC damage Blood cells injury others TF or other procoagulant components releasing Activate coagulation cascade Fibrin deposit  thrombosis Secondary fibrinolysis Bleeding Shock Hemolytic AnemiaMODS FDP formation Clotting factors consumption Hypocoagulable Hypercoagulable

34. Types and stages of DIC

35. Stages Hypercoagulable stage Hypercoagulable stage Hypocoagulable stage Hypocoagulable stage Secondary fibrinolytic stage Secondary fibrinolytic stage

36. Activation of Coagulation Fibrin monomer (FM) Secondary fibrinolysis FDP (X fragment) soluble fibrin monomer complex （ SFMC ） Protamine Sulfate FM polymerization X fragment positive 3P Test Plasma Protamine Paracoagulation

37. D-dimer formation

39. Types The form of DIC depends on the rapidity and force of the initiating event, leading to the two primary forms of DIC: Acute decompensated DIC Chronic compensated DIC Compensated DIC: When the stimulus for coagulation is mild, the liver can increase production of clotting factors to up to 5 times the normal rate, in an effort to maintain plasma levels. Similarly, platelet production can increase up to 10 times. Thus, although coagulation and fibrinolysis are in progress, platelet counts and fibrinogen levels may be normal or only marpinally reduced. These patients rarely bleed spontaneously or from minor trauma, but have severe haemorrhage if subjected to surgery.

40. Treatment of DIC

41. Cornerstone of management is the treatment of the underlying illness Supportive management with ▲ Disruption of coagulation cascade using “lower dose” heparin-treatment, administration of ATIII and/or activated protein C (protein C infusion has shown to be the first intervention proven to be effective in reducing the mortality in septic patients ▲ If bleeding is the predominant symptom Platelet infusion Coagulation factor substitution with fresh frozen plasma